Alkylation of phthalimide

Alkylation of phthalimide The Gabriel synthesis (Section 22 8) The potassium salt of phthalimide reacts with alkyl hal ides to give N alkylphthalimide deriva fives Hydrolysis or hydrazinolysis of this derivative yields a primary alkylamine... 

The alkylation of phthalimide has been carried out under phase-transfer conditions by Landini and Rolla,272 using soluble phosphonium salts and later by Tundo,273 using heterogenous phase transfer catalysts immobilized on silica gel. Later the preparation of N-alkylphthalimide has been carried out directly from phthalimide by Santaniello and Ponti.274... 

Polystyrene-bound amines can be converted into the corresponding phthalimides by heating with other phthalimides (BuOH, 85 °C, 18 h [33]). Support-bound phthalimides have also been prepared by N-alkylation of phthalimide derivatives [295] or by amidomethylation of cross-linked polystyrene with /V-(hydroxymethyl) or /V-(chloro-methyl)phthalimide [296,299]. 

Bogd, D., Pielichowski, J., and Boron, A. 1996. Remarkable fast microwave-assisted A -alkylation of phthalimide in dry media. Synlett, 873-74. 

The facile alkylation of phthalimide and subsequent hydrolysis of the N-substituted derivatives furnishes a convenient synthesis for primary amines. The substituted phthalimide was originally prepared by heating a mixture of phthalimide, potassium carbonate, and organic halide in a non-polar solvent for 2 to 24 hours at 100° to 150°. An improved procedure consists in performing this initial step in a polar solvent like dimethylformamide, in which potassium phthalimide is appreciably soluble the reaction occurs at room temperature within 10 minutes. Various esters of p-toluenesulfonic acid may be substituted for the organic halides as alkylating agents. ... 

The Gabriel synthesis is a classical but still useful procedure for the preparation of primary amines. The method consists of alkylation of phthalimide anion with an appropriate alkylating reagent and subsequent removal of the phthaloyl group to generate primary amines (Scheme 36). ... 

Alkylation of phthalimide anion can be carried out under solid-liquid phase-transfer conditions, using phosphonium salts or ammonium salts. In the reaction systems using hexadecyltributylphosphonium bromide, alkyl bromides and alkyl methanesulfonate are more reactive than alkyl chlorides. Octyl iodide is less reactive than the corresponding bromide and chloride. ( )-2-Octyl methanesulfonate was converted into (S)-2-octylamine with 92.5% inversion. Kinetic resolution of racemic ethyl 2-bromopro-pionate by the use of a chiral quaternary ammonium salt catalyst has been reported. Under liquid-liquid phase-transfer conditions, A -alkylation of phthalimide has been reported to give poor results. ... 

The alkylation of phthalimide can also be accomplished with G-alkylisoureas and alkoxyphosphonium salts. Thus, the reaction of (9-alkyl-A(A -cyclohexylisourea with phthalimide aflbrded (V-alkylphthai-imides in 60-70% yields (DMF, 120 C, 2-24 h). Starting from (/ )-2-octyiisourea, (S)-2-octylamine was obtained in 97.6% ee, indicating 98% inversion of the configuration took place. ... 

The reactions involving alkoxyphosphonium salts are also efiective for the A(-alkylation of phthalimide with virtually complete inversion of the secondary methanol center. Thus, the reaction of (S)-alcohol (81) with phthalimide, DEAD and triphenylphosphine afforded (82), which was subjected to a sequence of reactions to yield (2/ ,5f )-diamine (83) and the (2/ ,5Sj-isomer in a ratio of 99.4 0.6. The secondary... 

Although alkylation of phthalimide can now be performed under mild conditions as described in the preceding section, the final deprotection step still requires somewhat drastic conditions, e.g. the use of strong acid or base, or, alternatively, hydrazinolysis, at elevated temperature, due to the inherent stability of the phthaloyl group. This has prompted investigation of a number of alternatives to phthalimide which afford iV-alkyl derivatives amenable to milder deprotection. 

Table 18. N-Alkylation of phthalimide using K2CO3, TBAB...

The first step of the classical Gabriel synthesis (N-alkylation of phthalimide) gave excellent results under solid-liquid PTC conditions Lower yields are obtained under liquid-liquid PTC conditions, due to hydrolytic reactions. 

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